Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 20, Issue 5, 2020

Background: Food is indispensable for human life and determines the health and wellbeing of the consumer. As food is the source of energy for humans, it also emerges as one of the most important sources of exposure to deleterious chemicals both natural and synthetic. The food exposed chemicals cause a number of detrimental health effects in humans, with endocrine disruption being of serious concern amongst these effects. Such chemicals disrupting the health of endocrine system are known as endocrine-disrupting chemicals (EDCs). The food exposed EDCs need to be identified and classified to effectuate a cautious consumption of food by all and especially by vulnerable groups. Aim: The aim of the present review was to discuss food as a source of exposure to common endocrine disruptors in humans. This review presents the occurrence and levels of some of the critical endocrine disruptors exposed through frequently consumed diets. Methods: The major source of data was PubMed, besides other relevant publications. The focus was laid on data from the last five years, however significant earlier data was also considered. Conclusion: The food as a source of endocrine disruptors to humans cannot be neglected. It is highly imperative for the consumer to recognize food as a source of EDCs and make informed choices in the consumption of food items.

Background: Both the morbidity and mortality rates from congestive heart failure (CHF) remain elevated despite the medical and non-medical management of the disease, thus suggesting the existence of residual risk factors such as thyroid dysfunction. Particularly, the 15-30% of patients with CHF, especially those with severe ventricular dysfunction, display the so-called low T3 syndrome (LT3S), which seems to negatively affect the cardiovascular prognosis. Objective: Only a few clinical trials have been carried out to verify both the safety and the efficacy of thyroid replacement in the LT3S, aiming to ameliorate the prognosis of CHF, and most of the results were controversial. Methods: Since the aim of the present review was to briefly overview both the indication and contraindication of triiodothyronine replacement in CHF and LT3S, the authors searched PubMed using the medical subject headings (MeSH) related to the following terms: “congestive heart failure” and “low T3 syndrome” or “euthyroid sick syndrome” or “non-thyroidal sick syndrome”. The research study only focused on the narrative and systematic reviews, randomized clinical trials and meta-analysis studies which were conducted before June 2019. Results: Studies conducted in both animal models and humans provided controversial information about the effectiveness and safety of the T3 replacement for improving ventricular dysfunction, particularly in the long-term. Conclusion: Further clinical trials are needed to better explore the role of LT3S in patients with CHF and its consequent therapeutic strategy in this clinical setting.

Mast cells (MCs) have recently been re-interpreted in the context of the immune scenario in the sense that their pro-allergic role is no longer exclusive. In fact, MCs even in steady state conditions maintain homeostatic functions, producing mediators and intensively cross-talking with other immune cells. Here, emphasis will be placed on the array of receptors expressed by MCs and the variety of cytokines they produce. Then, the bulk of data discussed will provide readers with a wealth of information on the dual ability of MCs not only to defend but also to offend the host. This double attitude of MCs relies on many variables, such as their subsets, tissues of residency and type of stimuli ranging from microbes to allergens and food antigens. Finally, the relationship between MCs with basophils and eosinophils will be discussed.

Mast cells (MCs) bear many receptors that allow them to respond to a variety of exogenous and endogenous stimuli. However, MC function is dual since they can initiate pathological events or protect the host against infectious challenges. The role of MCs in disease will be analyzed in a broad sense, describing cellular and molecular mechanisms related to their involvement in auto-inflammatory diseases, asthma, autoimmune diseases and cancer. On the other hand, their protective role in the course of bacterial, fungal and parasitic infections will also be illustrated. As far as treatment of MC-derived diseases is concerned, allergen immunotherapy as well as other attempts to reduce MC-activation will be outlined according to the recent data. Finally, in agreement with current literature and our own data polyphenols have been demonstrated to attenuate type I allergic reactions and contact dermatitis in response to nickel. The use of polyphenols in these diseases will be discussed also in view of MC involvement.

Background: The present study aims to compare the relative efficacy and safety of different uses of cyclophosphamide (CYC) in lupus nephritis (LN). Methods: We searched the Cochrane Library, EMBASE, Global Health, MEDLINE and PubMed for articles from the database till June 2018. Results: 12 randomized controlled trials with 994 participants were included. The meta-analysis indicated that the short-interval lower-dose intravenous CYC regime remarkably reduced 24-hour proteinuria [mean difference (MD) -0.45; 95% confidence interval (CI) -0.62 to -0.27; I2 0%], incidence of major infections [odds ratio (OR) 0.62, 95% CI 0.40 to 0.95; I2 42%], gonadal toxicity (OR 0.41, 95% CI 0.27 to 0.62; I2 0%), and leukopenia (OR 0.55, 95% CI 0.33 to 0.94, I2 0%), while high-dose regime had an obvious lower probability of doubling of serum creatinine (Scr) level (OR 2.43; 95% CI 1.19 to 4.95; I2 0%). However, the difference in the complete and total remission rates between the two regimens was not observed. Conclusion: The result suggested that the short-interval lower-dose CYC regime remarkably reduced 24-hour proteinuria and the incidence of adverse events, while the long-course high-dose regime played a significant role in reducing the rate of doubling Scr level.

Background: Metabolic syndrome worsens complications in psoriasis patients by predisposing them to cardiovascular diseases. Psoriasis has been widely associated with metabolic syndrome; however, it has still not been proven owing to a limited number of studies and some of those reporting conflicting results. Objective: Psoriasis has reportedly been associated with metabolic syndrome; however, it has yet not been established beyond doubt owing to conflicting literature. The present meta-analysis of observational studies aims to evaluate the prevalence of metabolic syndrome in psoriasis patients and establish an inferring point that psoriasis patients are certainly susceptible to metabolic syndrome. The study will benefit clinicians to assess and monitor psoriasis patients for several associated comorbid conditions and in its treatment. Methods: A systematic web search for ‘Psoriasis’, ‘Metabolic Syndrome’, ‘Hypertension’, ‘Plasma Glucose’, ‘Dyslipidaemia’, ‘Waist Circumference’ was performed, collecting all original observational studies on humans up to April 30, 2018. Depending on the inclusion and exclusion criteria, articles were screened for eligibility. Due to the presence of significant heterogeneity, the Odds Ratio (OR) was calculated using a random-effect model with Der-Simonian and Laird method. The statistical heterogeneity was determined using I2 statistics. Comprehensive Meta-Analysis Software, Version 3 was used to perform all the analysis. Results: Sixty-three studies encompassing 15,939 psoriasis patients and 103,984 controls were included in this meta-analysis. Among them, 30.29 % of psoriasis patients were reported with metabolic syndrome in comparison to 21.70 % of subjects in the control group. The present study clearly indicates an increased prevalence of metabolic syndrome among psoriasis patients (OR: 2.077 [95% CI, 1.84 - 2.34]). Conclusion: The findings support the fact that psoriasis patients have a higher incidence of metabolic syndrome. Our study also recommends that psoriasis patients should be regularly monitored for metabolic syndrome complications and its associated risk factors such as hypertension, raised triglyceride, lowered HDL Cholesterol, increased fasting plasma glucose, and waist circumference.

Objective: Recent trial studies have found that resveratrol supplementation beneficially reduces oxidative stress marker, but, there is no definitive consensus on this context. The present systematic review and meta-analysis aimed to investigate the effect of resveratrol supplementation on oxidative stress parameters. Methods: We searched databases of Pubmed, Scopus and Cochrane Library up to December 2018 with no language restriction. Studies were reviewed according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) and Cochrane handbook. To compare the effects of resveratrol with placebo, weighted mean difference (WMD) with 95% confidence intervals (CI) were pooled based on the random-effects model. Results: Among sixteen clinical trials, we found that resveratrol supplementation increased GPx serum levels significantly (WMD: 18.61; 95% CI: 8.70 to 28.52; P<0.001) but had no significant effect on SOD concentrations (WMD: 1.01; 95% CI: -0.72 to 2.74; P= 0.25), MDA serum levels (WMD: -1.43; 95% CI: -3.46 to 0.61; P = 0.17) and TAC (WMD: -0.09; 95% CI: -0.29 to 0.11; P = 0.36) compared to placebo. Finally, we observed that resveratrol supplementation may not have a clinically significant effect on oxidative stress. Conclusion: However, the number of human trials is limited in this context, and further large prospective clinical trials are needed to confirm the effect of resveratrol supplement on oxidative stress markers.

Background: Type 2 Diabetes Mellitus (T2DM) is considered a chronic noncommunicable disease in which oxidative stress is expected as a result of hyperglycaemia. One of the most recent approaches is the study of microalgae fatty acids and their possible antioxidant effect. Objective: This study aimed to analyse the effect of supplementation with n-3 fatty acids extracted from microalgae on the total antioxidant capacity (TAC) and lipid peroxidation of adipose tissue and plasma from diabetic (db/db) and healthy (CD1) mice. Methods: Mice were supplemented with lyophilized n-3 fatty acids extracted from microalgae or added to the diet, from week 8 to 16. TAC assay and Thiobarbituric Acid Reactive Substances assay (TBARS) were performed on adipose tissue and plasma samples. Results: The supplementation of lyophilized n-3 fatty acids from microalgae increased the total antioxidant capacity in adipose tissue of diabetic mice (615.67μM Trolox equivalents vs 405.02μM Trolox equivalents from control mice, p<0.01) and in the plasma of healthy mice (1132.97±85.75μM Trolox equivalents vs 930.64±32μM Trolox equivalents from modified diet mice, p<0.01). There was no significant effect on lipid peroxidation on both strains. Conclusion: The use of n-3 fatty acids extracted from microalgae could be a useful strategy to improve total antioxidant capacity in T2DM.

Objective: The objective of the study was to evaluate the antihypertensive activity of Asteriscus graveolens. Methods: L-NAME hypertensive and normotensive rats have received orally the aqueous extract of Asteriscus graveolens aerial parts (AGAPE) (100 mg/kg) during six hours for the acute experiment and during seven days for the sub-chronic treatment. Thereafter, blood pressure parameters were evaluated. Concerning the in vitro investigation, the vasorelaxant effect of AGAPE was tested in isolated thoracic aortic rings. Results: AGAPE extract significantly decreased the blood pressure parameters in hypertensive rats. Moreover, the results revealed that AGAPE exhibited antihypertensive effect through its vasorelaxant properties. More interestingly, this vasorelaxant activity seems to be probably mediated through activation of K+ ATP-sensitive (KATP) channels. Conclusion: The study demonstrates the antihypertensive activity of aqueous Asteriscus graveolens extract in hypertensive rats through activation of vascular KATP channels. This finding supports the use of this plant for the management of hypertension in Morocco.

Background: Insulin resistance (IR) is an independent cardiovascular risk factor. IR predisposes to metabolic syndrome and diabetes. Meanwhile, little evidence exists about the effect of levothyroxine replacement treatment (LRT) on IR in hypothyroid patients. Objective: To investigate metabolic and anthropometric indices of IR in hypothyroid patients before and after 8 weeks of LRT. Methods: This pre-post study evaluated the 8 weeks outcomes of LRT on 66 patients with recently diagnosed hypothyroidism. Outcome measures included body mass index (BMI), waist circumferences (WC), waist to hip ratio (WHR), waist to height ratio (WHtR), body fat percent (BF%), free thyroxin (FT4), triglyceride (TG), low density lipoprotein (LDL), fasting plasma levels of glucose (FPG) and insulin. Sex- specific cut offs of two metabolic indices i.e. the triglyceride-glucose (TyG) and the homeostasis model assessment (HOMA) were used for IR diagnosis. The changes in TyG and HOMA were also compared after LRT. Results: Participants were overt and subclinical hypothyroidism 71% and 29%, respectively. After LRT the mean values of the following anthropometric indices significantly decreased: weight (79.61 vs. 78.64), BMI (29.53 vs. 29.2), WC (98.25 vs. 97.39) and BF% (35.34 vs. 34.95). After LRT the HOMA and TyG had no significant changes relative to their initial values. Also, IR that was determined on the basis of these metabolic indices more commonly observed in participants. Conclusion: Despite decreasing some anthropometric indices, the diagnosis of IR based on metabolic indices increased following 8 weeks LRT in hypothyroid cases.

Objective: To investigate the relationship between Interleukin-1beta (IL-1beta) and diabetic peripheral neuropathy (DPN) using animal models. Methods: The rat model of diabetic neuropathy was induced by intraperitoneal injection of a single dose of streptozotocin (STZ) at 65mg/kg. Diabetic rats were randomly divided into two groups (10 each), one treated with 0.9% saline (DMS group) and the other with interleukin-1 receptor antagonist (IL-1RA) at 50mg/kg (DMI group) twice a day for 5 weeks. Ten normal rats matched for weight, age and sex served as normal controls (Con group) and were treated with saline. Morphologic studies of sciatic nerves were achieved using light and transmission electron microscopy. Results: Transmission electron microscopy of the sciatic nerve showed the ultrastructure of myelin and the axon in the IL-1RA group was highly protected compared to diabetic controls. Conclusion: High levels of circulating IL-1beta may be associated with the risk of DPN and anti-IL-1 treatment may provide a potential strategy for the prevention of diabetic neuropathy.

Aims: Experimental and clinical evidence demonstrate that progesterone hormone and its nuclear receptor, the Progesterone Receptor (PR), play critical role in controlling mammary gland tumorigenesis and breast cancer development. Hormonal therapy (Tomaxifen) is the frontline treatment for hormone-dependent breast cancers. Progesterone hormone induces its action on the target cells by binding with its Progesterone receptor (PgR) therefore any genetic variations, which might induce alienation in the progesterone receptor, can result in an increased susceptibility of gynecological cancers. Alu insertion (PROGINS) mutation in PgR gene is reported to be associated with an increased risk of ovarian cancer and a decreased risk of breast cancer. However, its association with breast cancer risk remains inconclusive. Therefore, we investigated the association of PROGINS allele and its link with breast cancer risk. Methods: This case control study was performed on 200 subjects in which 100 were breast cancer cases and 100 gender matched healthy controls.The mutation was detected by using mutation specific PCR and results were confirmed by direct Sanger sequencing. Results: A clinically significant difference was reported in genotype distribution of PROGINs allele among the cases and gender-matched healthy controls (P<0. 032). Genotype frequencies of A1/A1, A1/A2, A2/A2 reported in cases was 81%, 19% (18% & 1%) and in matched healthy controls were 93%, 7% (6% & 1%). The higher frequency of PROGINs allele (19%) was observed in cases than the healthy controls (7%). The findings indicated that PgR variants (CC vs CT) increased the risk of Breast cancer in codominant inheritance model with OR= 3.44, 95% CI =1. 30-9.09, P<0.021) whereas nonsignificant association was found for CC vs TT genotypes with OR=1.14, 95% CI=0.07-18.658, P=0. 92. However, subgroup analysis revealed that CT + TT vs CC genotype increased the risk of breast cancer in dominant inheritance model tested OR = 3. 11, 95% CI = (1.24-7.79), P = 0.015). A nonsignificant association for PgR (CC+CT) vs TT) genotypes were reported in breast cancer OR = 1. 0, 95% CI= (0. 061-16.21), P=1) in recessive inheritance model tested. However, analysis with clinicalpathological variables revealed that the PROGINs allele is significantly associated with the distant metastasis and advanced stage of the disease. Conclusion: The mutation specific PCR was successfully developed as an alternative to Sanger sequencing for the cost-effective detection for PROGINS allele of progesterone receptor gene. A clinically significant correlation of PROGINs allele was reported with the distant metastasis and advanced stage of the disease. Taken together, these results demonstrated that PROGINS variant is associated with an increased susceptibility to Breast cancer, providing novel insights into the genetic etiology and underlying biology of Breast carcinogenesis. Further studies with large sample sizes are required to validate our findings.

Background: Previous clinical studies have suggested that apolipoprotein M (apoM) is involved in glucose metabolism and plays a causative role in insulin sensitivity. Objective: The potential mechanism of apoM on modulating glucose homeostasis is explored and differentially expressed genes are analyzed by employing ApoM deficient (ApoM-/- ) and wild type (WT) mice. Methods: The metabolism of glucose in the hepatic tissues of high-fat diet ApoM-/- and WT mice was measured by a glycomics approach. Bioinformatic analysis was applied for analyzing the levels of differentially expressed mRNAs in the liver tissues of these mice. The insulin sensitivity of ApoM-/- and WT mice was compared using the insulin tolerance test and the phosphorylation levels of protein kinase Akt (AKT) and insulin stimulation in different tissues were examined by Western blot. Results: The majority of the hepatic glucose metabolites exhibited lower concentration levels in the ApoM-/- mice compared with those of the WT mice. Gene Ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that ApoM deficiency affected the genes associated with the metabolism of glucose. The insulin tolerance test suggested that insulin sensitivity was impaired in ApoM-/- mice. The phosphorylation levels of AKT in muscle and adipose tissues of ApoM-/- mice were significantly diminished in response to insulin stimulation compared with those noted in WT mice. Conclusion: ApoM deficiency led to the disorders of glucose metabolism and altered genes related to glucose metabolism in mice liver. In vivo data indicated that apoM might augment insulin sensitivity by AKT-dependent mechanism.

Background and Objective: Endothelial-mesenchymal transition (EndMT) not only occurs during embryonic development, but also contributes to various diseases including cardiovascular diseases, fibrosis, and even cancer. However, the specific molecular biological mechanism and relationship of related pathways have not been fully elucidated. This study aims to explore the inhibitory effect of HGF on EndMT and the molecular mechanism of Notch signal in this process. Methods: HUVECs were treated with TGF-β1 and/or HGF for 72 hours. Expression levels of EndMT markers and the key transcriptional regulators of Notch signaling pathway were assessed by qRT-PCR and western blotting. C-Met expression was measured by qRT-PCR. Results: CD31 was downregulated and α-SMA, FSP1 were upregulated during TGF-β1-induced EndMT. HGF treatment significantly attenuates the development of TGF-β1-induced EndMT by down-regulating the signal transduction of the Notch signal pathway. Conclusion: This study proves that HGF treatment significantly attenuates the development of TGF- β1-induced EndMT by inhibiting the Notch signaling, which may provide new theoretical basis for the treatment of vascular diseases and numerous fibrotic diseases caused by EndMT.

Background: Potassium status has been found to affect glucose homeostasis. Objective: This study therefore aimed at investigating relationships between potassium status or dietary intake and fasting plasma glucose (FPG) or glycated haemoglobin (HbA1c) in a sample of Austrian adults (18-80 years, n = 421, 61% women) from the Austrian Study on Nutritional Status 2012. Methods: Dietary potassium intake was obtained by two 24 h recalls. FPG, plasma K+, and urinary K+ were determined photometrically, HbA1c by HPLC. Associations between the parameters were studied using multiple regression analysis after controlling for confounders and after age stratification of the sample (18-64 y vs. 65-80 y). Results: Most of the participants had a potassium intake of less than the estimated adequate daily intake of 4000 mg/d. In the multiple regression analyses in the whole sample plasma K+ had a statistically significant positive effect on FPG only in the crude model (β = 0.128, p < 0.01) and on HbA1c also in the fully adjusted model (β = 0.129, p < 0.05). The small effects on HbA1c were also detected in the younger age group but were absent in the older population. However, in this latter, a reverse association of urinary K+ on HbA1c was observed as well as of dietary potassium intake on FPG with no effects in the younger sample. Conclusion: We suggest that age dependent differences in the association between parameters of potassium status and blood glucose regulation should also be taken into account.

Background: Limited studies have been carried out with prednisone (PRED) in treatment by glucose intolerant individuals, even in this model the animals presented low blood glucose levels at adulthood, by the high regenerative capacity of β-cell. Objective: The aim was to evaluate the effects of the treatment of PRED in mild diabetes on biochemical and immunological biomarkers. Methods: Rats were randomly divided into four groups: control (C), treated control C+PRED (treatment of 1.25 mg/Kg/day PRED); diabetic DM (mild diabetes) and treated diabetic DM+PRED (treatment with same dose as C+PRED group). Untreated groups received vehicle, adjusted volume to body weight. The treatment lasted 21 days and measured body weight, food and water intake, and glycemia weekly. In the 3rd week, the Oral Glucose Tolerance Test (OGTT) and the Insulin Tolerance Test (ITT) was performed. On the last day, the rats were killed and the blood was collected for biochemical analyzes, leukogram and immunoglobulin G levels. Results: There was a significant decrease in body weight in mild diabetes; however, the treatment in diabetic groups increased food intake, glycemia, and the number of total leukocytes, lymphocytes and neutrophils. On the other hand, it decreased the levels of triglycerides, high-density and very lowdensity lipoproteins. In addition, diabetic groups showed glucose intolerance and mild insulin resistance, confirming that this model induces glucose intolerant in adult life. Conclusion: The results showed that the use of prednisone is not recommended for glucose intolerant individuals and should be replaced in order to not to aggravate this condition.